There has been remarkable progress in identifying the genetic basis for many types of inherited neurodegenerative disease. Despite this progress, genetic factors that contribute to the cause and progression of sporadic neurodegenerative disease remain generally unknown. Furthermore, in most instances, the genetic factors that influence the age of onset and rate of progression for many forms of inherited neurodegenerative disease remain to be identified. A better understanding of the genetic factors that are involved in neurodegenerative disease may not only help elucidate disease cause and progression, but could greatly expand the repertoire of molecular targets that are available for generating novel therapeutic interventions. We have performed an unbiased forward genetic screen for genes that cause neuromuscular degeneration when deleted, and for genes that slow the progression of neurodegeneration caused by neuronal stress or injury. In so doing, we have identified a novel, neuronally expressed, transcription factor that causes neuromuscular degeneration when deleted. Additional preliminary data demonstrate that this transcription factor regulates two downstream genes that are directly involved in neuromuscular stabilization versus degeneration: a secreted proteinase and a previously uncharacterized cell adhesion molecule. The proteinase is over-expressed and increased proteinase levels drive neurodegeneration. The cell adhesion molecule, when knocked down, causes neuromuscular degeneration. Thus, we have the potential to define the function of several new genes in the mechanisms of neuromuscular degeneration. We hypothesize that these molecules, taken together, represent a transcriptional program that determines whether motoneurons will remain stable or whether they will be destined to degenerate. As such, this system could be directly relevant to the factors that contribute to the cause and rate of progression of diverse neurodegenerative disorders.